REVIEW

Angiotensin-Converting Enzyme Inhibition: BeyondBlood Pressure Control—The Role of Zofenopril

Claudio Borghi . Stefano Omboni

Received: June 15, 2020 / Published online: August 8, 2020� The Author(s) 2020

ABSTRACT

The extensive use of angiotensin-convertingenzyme inhibitors (ACEIs) as antihypertensiveagents and the huge amount of data collected inclinical trials and post-marketing studies hasallowed the extending of the indication ofACEIs beyond blood pressure control. Currentguidelines recommend ACEIs in symptomaticpatients with heart failure with reduced ejectionfraction to decrease the risk of heart failurehospitalization, and also in patients after acutemyocardial infarction (AMI) with ST-elevationwith or without post-AMI ventricular dysfunc-tion. Analyzing the association between thechoice of an ACEI after AMI with the risk ofmortality and re-infarction, a class effect, ratherthan the superiority of some agents, has been

described. The focus of this review is centeredon the role of ACEIs in addition to and beyondblood pressure control. It summarizes clinicalevidence on the use of these agents in cardio-vascular diseases, with a specific interest in theexperience with zofenopril, which presents apeculiar pharmacological profile that may con-tribute to additional clinical benefits in someidentifiable populations of patients. Indeed, thepresence of a sulfhydryl group in its structureconfers on zofenopril high anti-oxidant andanti-ischemic properties involving the activa-tion of the H2S system, resulting in a cardio-protective effect. The efficacy and safety ofzofenopril have been extensively evaluated andproved in the Survival of Myocardial InfarctionLong-Term Evaluation (SMILE) program innumerous clinical settings. The pharmacologi-cal features and ancillary characteristics ofzofenopril with potent cardioprotective effectsseem to differentiate it from other ACEIs and toconfer further benefits to patients.

Keywords: ACE inhibitor; Bradykinin;Myocardial infarction; SMILE study; Sulfhydrylgroup; Zofenopril

Digital Features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.12687935.

C. Borghi (&)Unit of Internal Medicine, Policlinico S. Orsola,University of Bologna, Bologna, Italye-mail: claudio.borghi@unibo.it

S. OmboniClinical Research Unit, Italian Institute ofTelemedicine, Varese, Italy

S. OmboniScientific Research Department of Cardiology,Science and Technology Park for Biomedicine,Sechenov First Moscow State Medical University,Moscow, Russian Federation

Adv Ther (2020) 37:4068–4085

https://doi.org/10.1007/s12325-020-01455-2

Key Summary Points

Angiotensin-converting enzymeinhibitors (ACEIs) are currentlyrecommended for managing arterialhypertension, the progression of chronicrenal disease, post-myocardial infarction,congestive heart failure, and type 2diabetes mellitus.

In patients with acute or chronic coronarysyndrome and heart failure ACEIs appearto provide several benefits beyond bloodpressure control.

Among the various drugs of this class,zofenopril, a lipophilic, sulfhydryl group-containing ACEI, seems to contribute toadditional clinical benefits in someidentifiable populations of subjects.

The clinical efficacy and safety ofzofenopril has been evaluated in morethan 3,600 post-acute myocardialinfarction patients with or without leftventricular dysfunction in the fourrandomized controlled trials of the SMILEprogram.

The pharmacological characteristics andancillary features of zofenopril withpotent cardioprotective activity seem todifferentiate it from other ACEIs and toconfer further benefits to patients.

INTRODUCTION

Given the consolidated clinical experience inthe use of therapies blocking the renin-an-giotensin system (RAS), angiotensin-convertingenzyme inhibitors (ACEIs) and angiotensin II-receptor blockers (ARBs) have become a first-line strategy for managing arterial hyperten-sion, the progression of chronic renal disease,post-myocardial infarction, congestive heartfailure, and type 2 diabetes mellitus [1, 2]. Theseresults have been generated by a large number

of randomized clinical trials and observationalpost-surveillance studies that have demon-strated the clinical efficacy of RAS blockade indaily practice and in patients with presumedRAS activation and without hypertension [2].The focus of this review is centered on the roleof ACEIs beyond blood pressure (BP) controland summarizes the clinical evidence on the useof these agents in patients with different set-tings of cardiovascular diseases (CVDs). Specificattention is paid to the experience withzofenopril because of its peculiar pharmacolog-ical properties, mainly related to the sulfhydrylgroup present in its molecular structure. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

RAS INVOLVEMENT IN CVD

The RAS is one of the main physiological systemresponsible for homeostatic control of arterialpressure, electrolyte balance, organ perfusion,and extracellular volume. Its modulation hasseveral important effects that mainly involveCVDs and renal disease [3]. The pathway isinitiated by renin which cleaves the N-terminalportion of angiotensinogen to form the bio-logically inactive decapeptide angiotensin I [4];this inactive peptide is then hydrolyzed by ACEwhich removes the C-terminal dipeptide inorder to form the octapeptide angiotensin II,biologically active as a vasoconstrictor [4].Angiotensin II is the primary effector of a vari-ety of RAS-induced physiological and patho-physiological actions. It interacts with 4receptor subtypes expressed in the CV system(vasoconstriction, increased BP, increased car-diac contractility, vascular and cardiac hyper-trophy), kidney (renal tubular sodiumreabsorption, inhibition of renin release), sym-pathetic nervous system, and adrenal cortex(stimulation of aldosterone synthesis), as well asin the lung and the gut where it plays aremarkable role in fluid balance and respiratoryfunction [5, 6].

Therefore, a dysregulation of RAS is reportednot only in essential hypertension and in the

Adv Ther (2020) 37:4068–4085 4069

response of CV and renal tissue to hypertensiveand non-hypertensive injury but also in manyother CV disorders [4]. Angiotensin II isinvolved in the development of both vascularand cardiac hypertrophy and remodeling, vas-cular damage, renal damage, and atherosclerosiswith a mechanism that is only partially depen-dent on elevated BP values. [4]. In congestiveheart failure (HF), the reduced cardiac functionand the renal under-perfusion related to areduced effective intravascular volume areresponsible for renin hypersecretion and sec-ondary aldosteronism, contributing to pul-monary congestion and development of edema.In these patients, angiotensin II increasesperipheral vascular resistance (cardiac afterload)and enhances progressive ventricular

dysfunction contributing to the progression ofheart failure [4].

ACEI and ARB medications both target RAS,and are recommended in the treatment of sev-eral types of CVD (Fig. 1). However, the optimalchoice between these two groups of medica-tions for the prevention of CVD is not wellestablished [3].

ACEIs prevent the conversion of angiotensinI to angiotensin II by competing with angio-tensin I for the active site of ACE. The reductionof angiotensin II formation decreases vasocon-striction and aldosterone secretion and increa-ses plasma renin. As a consequence, ACEIs canlower BP, total peripheral resistance, andsodium and water retention [7]. ACEIs alsoreduce both preload and afterload througharterial and venous dilation. These hemody-namic effects are particularly beneficial in thepresence of left ventricular dysfunction (LVD)[8]. One disadvantage of ACEIs is that thepresence of non-ACE pathways results in con-tinued low-level production of angiotensin II,despite the inhibition of ACE. ARBs are selectiveligands of AT1 receptors; these drugs achievetheir clinical goals bypassing the limitations ofACE escape phenomena and non-ACE sourcesof angiotensin II formation, despite theincreased blood angiotensin II levels due toblockade of AT1-mediated receptor internaliza-tion (Fig. 1) [3, 9].

ROLE OF ACEIS IN CVDACCORDING TO CURRENTGUIDELINES

ACEIs are widely prescribed to manage hyper-tension, and are recommended in recentguidelines (level of recommendation IA) as thebasis of antihypertensive strategies, given theirability to reduce BP and CV events in random-ized clinical trials [10]. The potency of ACEinhibition is influenced by the affinity of thedrug to the zinc (Zn??) ligand of ACE. Thereare three distinct chemical classes of ACEIs(Table 1): (1) sulfhydryl containing ACEIs (i.e.,captopril, zofenopril) which strongly bind theZn?? ligand, but disulfide formation limitstheir half-life; (2) drugs containing a carboxyl

Fig. 1 Renin-angiotensin system and related molecules.Many molecules influence the effects of renin-angiotensinsystem activation. Angiotensin II and AT1R are keymolecules of the major harmful pathway in the cardiovas-cular system. Counteracting pathways with cardiovascularprotective property also exist. There are controversiesabout the effects of AT2R signaling, which are indicated ingray italic [3]. ARB angiotensin receptor blocker, AT1Rangiotensin type one receptor, AT2R angiotensin type tworeceptor, AT3R angiotensin type three receptor, AT4Rangiotensin type four receptor, CAGE chymostatin-sensi-tive angiotensin-II-generating enzyme, MasR Mas receptor,MMP-8 matrix metalloproteinase-8, NEP neutralendopeptidase, PCP prolyl carboxypeptidase, PEP prolylendopeptidase, RAS renin-angiotensin system, VSMCvascular smooth muscle cell

4070 Adv Ther (2020) 37:4068–4085

Table1

Angiotensin-con

vertingenzymeinhibitorscurrently

indicatedforthetreatm

entof

cardiovascular

patients

Drug

Molecular

structure

Absorption

(%)

Half-

life(h)

Metabolism

Mainroute

of elim

ination

App

rovedindication

sHypertension

Heart

failu

re

Initial

daily

dose

(mg)

Maxim

aldaily

dose

(mg)

Initial

daily

dose

(mg)

Initial

daily

dose

(/mg)

Benazepril

Dicarboxylic

group

3710–1

1?

(benazeprilat)

Renal

Hypertension

1040

––

Captopril

Sulfh

ydryl

group

60–7

52

?Renal

Hypertension,

heartfailure,

post-AMIpatientswith

LVD,type1diabetic

nephropathy

12.5 (tid)

150(tid)

6.25 (tid)

150 (tid)

Cilazapril

Dicarboxylic

group

45–8

51.5–

2.0

?(cilazaprilat)

Renal

Hypertensionandheart

failure

1–1.25

50.5

5

Enalapril

Dicarboxylic

group

6011–1

4?

(enalaprilat)

Renal

Hypertensionandheart

failure

(orasym

ptom

atic

LVD)

540

2.5 (bid)

20(bid)

Fosinopril

Phosphonate

group

3612

?(fosinoprilat)

Renaland

hepatic

Hypertensionandheart

failure

1040

5–10

40

Lisinopril

Dicarboxylic

group

2512

–Renal

Hypertension,

heartfailure

andpost-AMI

hemodynam

ically

stablepatients

1040

2.5–

540

Moexipril

Dicarboxylic

group

132–

9?

(moexiprilat)

Renal

Hypertension

7.5

30–

–

Perind

opril

Dicarboxylic

group

65–7

51.2

?(perindoprilat)

Renal

Hypertensionand

stableCAD

patients

416

––

Quinapril

Dicarboxylic

group

50–8

02.3

?(quinaprilat)

Renal

Hypertensionandheart

failure

10–2

080

5(bid)

20(bid)

Adv Ther (2020) 37:4068–4085 4071

Table1

continued

Drug

Molecular

structure

Absorption

(%)

Half-

life(h)

Metabolism

Mainroute

of elim

ination

App

rovedindication

sHypertension

Heart

failu

re

Initial

daily

dose

(mg)

Maxim

aldaily

dose

(mg)

Initial

daily

dose

(mg)

Initial

daily

dose

(/mg)

Ram

ipril

Dicarboxylic

group

50–6

013–1

7?

(ram

iprilat)

Renal

Hypertension,

heartfailure

(post-AMI),h

ighrisk

CV

patients

2.5

202.5 (bid)

5(bid)

Trand

olapril

Dicarboxylic

group

40–6

016–2

4?

(trand

olaprilat)

Hepatic

Hypertenion

andpost-AMI

(CHFor

asym

ptom

atic

LVD

patients)

1–2

41

4

Zofenopril

Sulfh

ydryl

group

785.5

?(zofenoprilat)

Renal

Hypertensionandpost-AMI

(\24-h)

1560

––

Drug

Post-AMI

Other

indication

Initialdaily

dose

(mg)

Maxim

aldaily

dose

(mg)

Initialdaily

dose

(mg)

Maxim

aldaily

dose

(mg)

Benazepril

––

––

Captopril

6.25

(tid)

50(tid)

–25

(tid)

Cilazapril

––

––

Enalapril

––

––

Fosinopril

––

––

Lisinopril

510

––

Moexipril

––

––

Perind

opril

––

48

Quinapril

––

––

Ram

ipril

––

2.5

10

Trand

olapril

14

––

4072 Adv Ther (2020) 37:4068–4085

group (i.e., enalapril, lisinopril, ramipril) thatbinds to side chains of the enzyme within theactive moiety for improved potency and dura-tion of action; and (3) drugs composed ofphosphorus-containing ACEIs (i.e., fosinopril)[11, 12]. Although direct ACEIs comparisonsamong available agents are rare, a Cochranereview has demonstrated that there are noclinically meaningful differences in BP-loweringefficacy between different ACEIs [13].

ACEIs are the mainstay not only for hyper-tension management but also for other CVD,including HF, LVD, and acute myocardialinfarction (AMI) (Table 2). In HF, ACEIsdecrease total peripheral resistance, pulmonaryvascular resistance, pulmonary capillary wedgepressure, and mean arterial and right atrialpressures, thus resulting in reduced mortality,regardless of HF severity [7, 8]. In these patients,the use of ACEIs has been shown to increasecardiac index, cardiac output, stroke volume,and exercise tolerance [7]. Many pieces of evi-dence indicate that BP control delays the onsetof HF and, in some cases, contributes to pro-longing life, and this also applies to hyperten-sive patients treated with ACEIs with or withouta history of myocardial infarction, especially inolder people [14]. As per current guidelines, anACEI is recommended in addition to a beta-blocker for symptomatic patients with HF withreduced left ventricular ejection fraction (LVEF)to reduce the risk of HF hospitalization anddeath (recommendation 1A) [15]. A meta-anal-ysis of three randomized trials (SAVE, Survivaland Ventricular Enlargement; AIRE, AcuteInfarction Ramipril Efficacy; and TRACE, tran-dolapril in patients with reduced LVD afteracute myocardial infarction), including 5966patients with LVD or HF, have indicated thatadministration of ACEIs after AMI providesclear benefit and lead to substantial reductionsin mortality and morbidity in high-risk patients[16]. Indeed, the proportion of patients read-mitted for HF resulted was reduced by 27% withACEIs [11.9% in the ACEI group vs. 15.5% ofthe control group; hazard ratio (HR) 0.73 95%CI 0.63–0.85, p\ 0.0001], while the combina-tion of death or hospital admission for HFoccurred in 30.5% of the ACEI group and 37.0%of the control group [17]. ACEIs are alsoT

able1

continued

Drug

Post-AMI

Other

indication

Initialdaily

dose

(mg)

Maxim

aldaily

dose

(mg)

Initialdaily

dose

(mg)

Maxim

aldaily

dose

(mg)

Zofenopril

7.5(bid)

30(bid)

––

AMIacutemyocardialinfarction,

CAD

coronary

artery

disease,CVcardiovascular,C

HFcongestive

heartfailure,L

VD

leftventriculardysfun

ction,

bidtwice-a-day,

tidthree-times-a-day

Adv Ther (2020) 37:4068–4085 4073

Table 2 Current recommendations of the European Society of Cardiology for the use of angiotensin converting enzymeinhibitors in patient with cardiovascular disease

Class ofrecommendation

Level ofevidence

Recommendations for treating arterial hypertension [10]

Among all antihypertensive drugs, ACEIs, ARBs, BBs, CCBs, and diuretics (thiazides

and thiazide-like drugs such as chlorthalidone and indapamide) have demonstrated

effective reduction of BP and CV events in RCTs, and are thus indicated as the basis

of antihypertensive treatment strategies

I A

Combination treatment is recommended for most hypertensive patients as initial

therapy. Preferred combinations should comprise a RAS blocker (either an ACEI or

an ARB) with a CCB or diuretic. Other combinations of the five major classes can be

used

I A

It is recommended that if BP is not controlled with a two-drug combination,

treatment should be increased to a three-drug combination, usually a RAS blocker

with a CCB and a thiazide/thiazide-like diuretic, preferably as an SPC

I A

Recommendations for treating patients with symptomatic HF with reduced ejection fraction [15]

An ACEI is recommended, in addition to a BB, for symptomatic patients with HFrEF

to reduce the risk of HF hospitalization and death

I A

A BB is recommended, in addition to an ACEI, for patients with stable, symptomatic

HFrEF to reduce the risk of HF hospitalization and death

I A

An MRA is recommended for patients with HFrEF who remain symptomatic despite

treatment with an ACEI and a BB to reduce the risk of HF hospitalization and death

I A

Recommendations for treating chronic coronary syndrome [18]

ACEIs (or ARBs) are recommended if a patient has other conditions (e.g., HF,

hypertension, or diabetes)

I A

ACEIs should be considered in CCS patients at very high risk of CV events IIa A

Recommendations for treating STEMI [22]

ACEIs are recommended, starting within the first 24-h of STEMI in patients with

evidence of HF, LVSD, diabetes, or anterior AMI

I A

An ARB, preferably valsartan, is an alternative to ACEIs in patients with HF and/or

LVSD, particularly those who are intolerant to ACEIs

I B

ACEIs should be considered in all patients in the absence of contraindications IIa A

ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, BP blood pressure, BB beta-blocker,CCB calcium channel blocker, CCS chronic coronary syndrome, CV cardiovascular, HF heart failure, HFrEF heart failurewith reduced ejection fraction, LVSD left ventricular systolic dysfunction, MRA mineralocorticoid receptor antagonist, RASrenin-angiotensin system, RCT randomized controlled trial, SPC single-pill combination, STEMI ST-segment elevationmyocardial infarction

4074 Adv Ther (2020) 37:4068–4085

indicated in patients with asymptomatic LVsystolic dysfunction in order to minimize therisk of development of HF, and consequenthospitalization, and death [15].

In patients affected by coronary artery dis-ease (CAD) with preserved systolic ventricularfunction, the evidence for routine administra-tion has been conflicting. A metanalysis by Al-Mallah et al. reported a modest benefit of ACEIson the prognosis of patients with CAD associ-ated with preserved LV systolic function [17].Data from more than 33,000 patients indicatedthat ACEIs therapy, when added to conven-tional therapy (aspirin, beta-blockers, and sta-tins), was associated with a decrease in the rateof CV mortality (risk reduction or RR 0.83, 95%CI 0.72–0.96, p = 0.01), nonfatal MI (RR 0.84,95% CI 0.75–0.94, p = 0.003), all-cause mortal-ity (RR 0.87, 95% CI 0.81–0.94, p = 0.0003), andcoronary revascularization (RR 0.93, 95% CI0.87–1.00, p = 0.04) [17]. Not all trials, however,described an effective advantage in the use ofACEIs in this setting; hence, current guidelinesgenerally do not recommend ACEIs in chroniccoronary syndrome patients without HF or highCV risk, unless with coexisting hypertension,LVEF B 40%, diabetes, or chronic kidney dis-ease. In these latter cases, ACEIs should beconsidered (level of recommendation IIA) [18].

Therapy with ACEIs is also common afterAMI. Numerous trials have indicated that mor-tality and morbidity were reduced when ACEIswere administered in a relatively unselectedpopulation of patients in the acute phase of MI(‘‘early’’) or in patients with evidence of LVD inthe subacute phase after MI (‘‘late’’) [19]. In theirmetanalysis, Franzosi et al. collected data fromlarge randomized trials which evaluated theefficacy and safety of treatments with ACEIsgiven in the acute phase of MI (0–36 h from theonset of symptoms) and continued for a shortperiod of follow-up (generally 4–6 weeks) [20].These trials were CONSENSUS-II, GISSI-3, ISIS-3,and CCS-1, and included a total of 98,496patients. The main conclusions of the analysiswere: (1) ACEI treatment can be started imme-diately during the acute phase of MI, in associ-ation with other routinely recommendedtreatments (such as thrombolytics, aspirin, and

beta-blockers); (2) the benefit occurs during thefirst few days after MI, suggesting a positive roleof tissue remodeling; (3) the benefit is propor-tionally larger in higher-risk subgroups (thosewith an anterior site MI or high heart rate); and(4) early benefits would be complementary tothat observed later in trials of prolonged ACEItherapy initiated several days or weeks after MIin patients with evidence of HF or LVD [20].Due to the lack of clinical trials that directlycompared the efficacy of different ACEIs treat-ment after AMI, these drugs are generallyassumed to be equally effective [21]. Analyzingthe association between the choice of an ACEIafter MI with the risk for mortality and rein-farction, a class effect was described rather thana superiority of some agents, when drugs wereused in comparable dosages, thus suggestingthat it would be more important initiatingtreatment and continuing treatment at therecommended dosage than choosing a particu-lar agent to achieve long-term benefits [21].Current guidelines recommend ACEIs after AMIwith ST-elevation, starting within the first 24 hof ST-elevation myocardial infarction (STEMI)in patients with evidence of heart failure, LVsystolic dysfunction, diabetes, or an anteriorinfarct (level of recommendation IA). Theyshould be considered in all patients with AMIunless specifically contraindicated (level of rec-ommendation IIa) [22].

ACEIs are commonly used in patients withdiabetes and/or with renal disease. In a sys-tematic review including 36,917 participants(including 2400 deceased, 766 patients whorequired dialysis, and 1099 patients in whichserum creatinine levels doubled), ACEIs showedhigher probabilities of reducing all-cause mor-tality, use of dialysis, or doubling of serum cre-atinine levels, and demonstrated renoprotectiveeffects [23]. These observations were confirmedeven in chronic renal disease progression whenACEIs decreased BP, and urinary protein excre-tion slowed the increase in serum creatinineand reduced the risk for end-stage renal disease(ESRD), or for the combined outcome of dou-bling of the baseline serum creatinine concen-tration or ESRD by approximately 30% [24].

Adv Ther (2020) 37:4068–4085 4075

ZOFENOPRIL:A CARDIOPROTECTIVE ACEI

Zofenopril is a sulfhydryl ACEI featuring a highlipophilicity, long-lasting tissue penetration,selective cardiac ACEI, potent anti-oxidantactivities, and good efficacy after a single dailyadministration (Table 3) [25]. Starting from1990, its efficacy and safety have been evaluatedin the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) project, a large clinicalprogram aimed at investigating the role ofzofenopril in the treatment of AMI in severalpopulations of patients to test the hypothesisthat its unique pharmacological profile couldprovide some benefits beyond ACE inhibition,in terms of CV event prevention (Table 4). Thefirst trial was a pilot study that evaluated thesafety of zofenopril administration within 24 hof the onset of AMI symptoms and providedsome preliminary data of efficacy in terms ofcombined occurrence of death, non-fatal CVevents, and severe adverse events after a12-month follow-up [26]. A large clinical trialwas then designed to determine the efficacy of6-week zofenopril administration (15–60 mgtwice daily) versus placebo in 1556 patientswith MI not receiving thrombolysis and treatedwithin 24 h of the onset of symptoms (SMILE-1). The incidence of death or severe congestiveHF at 6 weeks (primary end-point) was signifi-cantly reduced in the zofenopril group, withrisk reduction by 34% (95% CI 8–54%;p = 0.018). These positive outcomes were

maintained after 1 year, observing a risk reduc-tion for death of 29% (95% CI 6–51%;p = 0.011) [27]. Given the large size of popula-tion involved in the SMILE trials, many statis-tically pre-specified and adequately poweredpost hoc analyses on specific subgroups couldbe performed, providing evidence on zofenoprileffects in older patients, and in patients witharterial hypertension [28], diabetes [29], hyper-cholesterolemia [30], metabolic syndrome [31],angina, or previous myocardial infarction orNSTEMI [32]. Zofenopril was then directlycompared with two ACEIs in randomized clini-cal trials carried out in patients with coronaryartery disease. In the SMILE-2 study, zofenoprilwas compared to lisinopril in 1024 patients withacute MI undergoing thrombolysis [33], whilein the SMILE-4 study, the main comparison wasbetween zofenopril and ramipril in combina-tion with acetylsalicylic acid (ASA) in patientswith post-MI left ventricular dysfunction. In theSMILE 2 trial, zofenopril slightly reduced theincidence of severe hypotension versus lisino-pril (10.9% vs. 11.7%, p = 0.38), with a signifi-cant decrease in the rate of drug-related severehypotension (6.7% vs. 9.8%, p = 0.048) withouta difference in mortality or major CV compli-cations [33]. SMILE-4 investigated whether thebenefits of zofenopril or ramipril could beaffected by a concomitant ASA administrationin patients with LV dysfunction after AMI [34].The occurrence of death or hospitalization forCV cause was significantly reduced withzofenopril (odds ratio: 0.70; 95% CI: 0.51–0.96;

Table 3 Pharmacological properties of sulphydrylic angiotensin-converting enzyme inhibitors[25]

Pharmacological properties Clinical effects

Higher lipophilicity and tissue penetration Effective prevention of CV events

Higher affinity and more persistent binding to tissue ACE

(cardiac, renal and vascular)

Effective prevention of CV events

Lesser Bk-dependent effect Good safety (reduced frequency of hypotension, cough, and

renal function deterioration)

Significant antioxidant effect Significant anti-ischemic effect

Increased release and availability of H2S Improved CV function

ACE angiotensin-converting enzyme, BK bradikinin, CV cardiovascular

4076 Adv Ther (2020) 37:4068–4085

Table4

Summaryof

maincharacteristicsandoutcom

esof

theSM

ILEStudies

Stud

yPeriodof

the

enrolm

ent

Inclusioncriteria

Intervention

(n)

Con

trol

(n)

Daily

zofeno

pril

dose

Con

trol

Treatment

duration

(weeks)

Post

treatm

ent

follo

w-up

(weeks)

SMILE

Pilot

1988–1

989

AMIwithlack

ofindication

forathrombolytic

therapy

101

103

15–3

0mg

Placebo

48–

SMILE-1

1991–1

992

AnteriorAMInoteligibleforthrombolytic

therapyin

theprevious

12h

772

784

15–6

0mg

Placebo

648

SMILE-2

1998–1

999

Throm

bolytictreatm

entwithin12

hfrom

AMI

andSB

P[

100mmHg

504

520

15–6

0mg

Lisinopril

2.5–

10mg

daily

6–

SMILE-3

1998–2

001

AMIin

thepreceding6weeks

withpreservedleft

ventricularejection

fraction

([40%),prior

thrombolysisandtreatm

entwithACEIs

172

177

15–6

0mg

Placebo

24–

SMILE-4

2005–2

009

AMIin

theprevious

24htreatedor

untreated

withPT

CA,w

ithclinicaland/or

echocardiographicevidence

ofleftventricular

dysfun

ction

365

351

15–6

0mg

plus

ASA

100

mgdaily

Ram

ipril

10mgdaily

plus

ASA

100mg

daily

48–

SMILE

Overall

1991–2

009

The

sameof

theSM

ILE-1

to-4

study

1808

1822

30–6

0mg

Placebo,

lisinoprilor

ramipril

6–48

–

Stud

yPrimaryend-po

int

Mainresults

Subgroup

sanalysis

SMILEPilot

Safety

oftreatm

ent

Goodtolerabilityof

zofenopril

SimilarCVmortalityto

placebo

Reduced

hospitalization

Improved

LVEF

–

Adv Ther (2020) 37:4068–4085 4077

Table4

continued

Stud

yPrimaryend-po

int

Mainresults

Subgroup

sanalysis

SMILE-1

Occurrenceof

deathor

severe

congestive

heartfailure

over

6weeks

Improved

short-term

6-weeks)and

long-term

(1-year)

outcom

e

Superior

efficacyof

zofenoprilcompared

toplacebo,

also

insubjectswithdiabetes,

hypercholesterolem

ia,m

etabolicsynd

rome,

hypertension

andNST

EMI

SMILE-2

Occurrenceof

severe

hypotension

(SBP\

90mmHg)

atanytime

Low

errate

ofsevere

hypotensionwith

zofenoprilcomparedto

lisinopril

–

SMILE-3

Globalischem

icburden

(ischemiaon

24-h

ambulatory

ECG,ischemiaor

angina

during

treadm

illtest,recurrent

AMI,

need

forrevascularization)

Zofenoprilsignificantlyreducedthefrequency

andseverity

ofexertionaland

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ACEIangiotensin-converting

enzymeinhibitor,AMIacutemyocardialinfarction,A

SAacetylsalicylicacid,C

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VEFleft

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fraction,N

STEMInon-ST

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minalcoronary

angioplasty,SB

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[26–

39]

4078 Adv Ther (2020) 37:4068–4085

p = 0.028), and this benefit was maintainedduring 5-year follow-up (Fig. 2) [34, 35]. Thesame results have been confirmed after apropensity analysis of the population andcomparing subpopulations of patients appro-priately matched for the main prognostic vari-ables [36]. Finally, the cardioprotective effectsof zofenopril were investigated in the SMILE-3ISCHEMIA trial in 349 patients with preservedLV function after MI. In these patients receivingrecommended standard treatment, zofenoprilreduced the global burden of myocardial ische-mia by decreasing the occurrence of significantST-T abnormalities on ambulatory electrocar-diography (ECG), ECG abnormalities or symp-toms of angina during the standard exercisetest, MI recurrence and the need for revascu-larization procedures, in comparison to placebo(20.3% vs. 35.9%, p = 0.01) (Fig. 3) [37]. Theresults were not affected by demography, BPcontrol, and concomitant pharmacologicaltreatment, and supported some primary car-dioprotective effect of zofenopril. Morerecently, the results of the SMILE-ischemiastudy were corroborated by a post hoc analysisof SMILE 4, stratifying patients by LVEF mea-sured at baseline, and showing a reduction in1 year and long-term mortality and hospital-ization in post-MI with preserved LV function(Fig. 4) [38]. The cardioprotective properties ofzofenopril were confirmed in a pooled analysisof the four SMILE studies [39] (Fig. 5).

THE RATIONALEOF THE CARDIOPROTECTIVEPROPERTIES OF ZOFENOPRIL

Zofenopril-mediated cardioprotection duringischemia/reperfusion seems to be associatedwith an increased H2S and nitric oxide (NO)signaling. Hydrogen sulfide is a cytoprotectivephysiological signaling molecule acting inconcert with NO and carbon monoxide in orderto maintain physiological homeostasis in boththe heart and circulation. Experimental evi-dence indicates that H2S donors, such aszofenopril, can attenuate the pathological con-sequences of myocardial ischemia/reperfusioninjury and HF, reducing oxidative stress and

inflammation and inhibiting apoptosis [40]. Inexperimental models, indeed, zofenopril pre-conditioning enhanced tissue antioxidantdefense, thus preventing reactive oxygen spe-cies formation, following an ischemic injuryduring reperfusion. Furthermore, treatmentwith zofenopril upregulated the expression ofantioxidant enzymes, such as Trx-1, GPx-1, andSOD-1, suggesting an enhancement in antioxi-dant defenses before ischemia that mitigatemyocardial reperfusion injury [41]. As summa-rized in Fig. 6, the enhanced H2S signaling,alongside the inhibition of angiotensin II for-mation and bradykinin metabolism, could rep-resent a further explanation of additionalbeneficial effects provided by zofenopril [40]. Inaddition, ex vivo animal studies indicated that,at the heart level, where ACE inhibition mayprevent ischemic damage, zofenopril produceda more striking and long-lasting ACE inhibitionthan ramipril and enalapril, and, to a lesserextent, than captopril and fosinopril; 60% ofACE inhibition could persist in the heart at least8 h after administration, while it was muchlower with other ACEIs [41]. Conversely, in thelung, zofenopril showed a lower potency inboth inhibiting ACE and reducing bradykininmetabolism [41]; bradykinin accumulation inthe airways with zofenopril is lower than thatobserved with other ACEIs, and this may par-tially explain the relatively low risk of coughingobserved with zofenopril (Fig. 7) [42]. Indeed, ameta-analysis including hypertensive and post-myocardial infarction patients indicated thatzofenopril-induced cough was generally of amild to moderate intensity, occurred signifi-cantly (p = 0.001) more frequently in the first3–6 months of treatment (3.0% vs. 0.2% 9–-12 months), and always resolved or improvedupon therapy discontinuation [39].

CONCLUSIONS

The pharmacological features of zofenoprilprovide cardioprotective, anti-ischemic, andanti-oxidant effects that differentiate it fromother ACEIs. Zofenopril was evaluated as anearly treatment after AMI, showing both short-and long-term benefits, and it has been

Adv Ther (2020) 37:4068–4085 4079

confirmed as a feasible and effective therapy inmany subgroups of patients with CV andmetabolic comorbidities. Therefore, as well asother ACEIs, zofenopril is recommended for themanagement of CVD, including HF, AMI, andLVD, beyond BP control. As per current guide-lines, ACEIs are recommended in symptomaticpatients with HF with reduced LVEF to reducethe risk of HF hospitalization and in patientsafter AMI with ST-elevation. Since the effect inreducing the risk of mortality and reinfarction isnot specifically associated with a single agent,and is rather described as a class effect, thechoice of ACEI therapy can be addressed by theancillary characteristics of each agent that mayconfer further benefits to patients.

Fig. 2 a Incidence of the combined end-point (cardiovas-cular mortality or hospitalization for cardiovascular causes)and b of hospitalization during the 1-year of treatmentwith ramipril plus acetylsalicylic acid (n = 351, dashedlines) or zofenopril plus acetylsalicylic acid (n = 365,continuous lines) in the SMILE-4 Study. c Incidence of thecombined endpoint and d hospitalization during the

follow-up in patients originally randomized and treatedwith zofenopril (continuous lines, n = 144) or ramipril(dashed lines, n = 121) in the SMILE-4 Study. p valuesfrom the log-rank statistics [34, 35]. RRR relative riskreduction, R ramipril, Z zofenopril

Fig. 3 Occurrence (%) of the different primary endpointsof the study after 6 months of treatment with placebo(n = 177, open bars) or zofenopril (n = 172, full bars) inthe patients of the SMILE-3 Study [37]. TT treadmill test,CABG coronary artery bypass graft, PTCA percutaneoustransluminal coronary angioplasty. p values refer to thestatistical significance of the between-treatment difference

4080 Adv Ther (2020) 37:4068–4085

Fig. 4 Cumulative survival without events during 1 yearin patients (a) with preserved systolic function (leftventricular ejection fraction[ 40%) and (b) withimpaired systolic function (left ventricular ejection frac-tion B 40%) treated with zofenopril (continuous line) orramipril (dotted line). c Odds ratio and 95% confidence

interval for 1-year combined occurrence of cardiovascularmortality or hospitalization for cardiovascular causesaccording to ranges of left ventricular ejection fraction[38]. CI confidence interval, LVEF left ventricular ejectionfraction, OR odds ratio, R ramipril, Z zofenopril

Fig. 5 a Cumulative survival and b cumulative survivalwithout cardiovascular events during 1-year of follow-up inpatients treated with placebo (n = 951, dashed lines), otherangiotensin-converting enzyme inhibitors (lisinopril orramipril, n = 871, dotted lines) and zofenopril (n = 1808,

continuous line) in the SMILE program. The relative riskreduction versus placebo is indicated. p values from a Coxregression model [39]. Z zofenopril, ACEI angiotensin-converting enzyme inhibitor, RRR relative risk reduction

Adv Ther (2020) 37:4068–4085 4081

ACKNOWLEDGEMENTS

Funding. Sponsorship for the SMILE pro-gramme and open access fee were funded byMenarini International Operations LuxembourgS.A. No Rapid Service Fee was received by thejournal for the publication of this article. Thefunding source did not influence or commentedon planned methods, protocol, data analysisand the paper. All authors had full access to allof the data in this study and take complete

responsibility for the integrity of the data andaccuracy of the data analysis.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Conflict of interest of ProfClaudio Borghi: consultancy for BoheringerIngelheim, Menarini International, Sanofi,

Fig. 6 Effect of zofenopril on hydrogen sulfide and nitricoxide bioavailability. By inhibiting myocardial angiotensin-converting enzyme activity, zofenopril reduces the gener-ation of angiotensin II and increases levels of bradykinin.Bradykinin, through stimulation of endothelial B2 recep-tors, promotes the release of nitric oxide, prostacyclin, andendothelium-derived hyperpolarizing factor, which in turnleads to cardioprotection. On the other hand, zofenopril,by releasing hydrogen sulfide, enhances tissue antioxidant

defense, and promotes activation of endothelial nitricoxide synthase, leading to increased levels of nitric oxide.Therefore, angiotensin-converting enzyme inhibition,hydrogen sulfide, and nitric oxide account for zofenopril-mediated cardioprotective effects [40]. ACE angiotensin-converting enzyme, BK bradykinin, EDHF endothelium-derived hyperpolarizing factor, eNOS endothelial nitricoxide synthase, H2S hydrogen sulfide, NO nitric oxide

4082 Adv Ther (2020) 37:4068–4085

Amgen, Takeda, Novartis, Ely Lilly and Servier.Stefano Omboni has nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not included

in the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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